While investigating a fungus known to cause an infection in people
with AIDS, two grantees of the National Institute of Allergy and
Infectious Diseases (NIAID), part of the National Institutes of
Health (NIH), unexpectedly discovered a potential strategy for
treating metastatic melanoma, one of the deadliest forms of skin
cancer. The treatment approach, which involves combining an antibody
with radiation, has since been further developed and is expected
to enter early-stage human clinical studies in 2007.

“This is an excellent example of how scientific research in one
discipline may have payoffs in a completely unpredictable way,” says
NIAID Director Anthony S. Fauci, M.D. “This important AIDS-related
research has led to the development of a promising therapeutic
strategy for a terrible cancer that affects thousands of people
each year.”

Arturo Casadevall, M.D., Ph.D., of the Albert Einstein College
of Medicine at Yeshiva University, in New York City, and his research
team began studying the biology of the skin pigment melanin to
better understand why its synthesis plays a role in the process
whereby certain yeastlike fungi, specifically Cryptococcus
neoformans, cause disease in some people. C. neoformans can
cause cryptococcosis, a potentially fatal fungal infection that
can lead to inflammation of the brain and death in people with
AIDS and other immunocompromised individuals.

The researchers created an infection-fighting (monoclonal) antibody
that binds to melanin, based on scientific evidence suggesting
that, when melanin is synthesized, it causes the immune system
to react in a way that might create antibodies to fend off C. neoformans
infection. Based on this finding, Dr. Casadevall theorized that
melanomas might contain melanin that would allow the monoclonal
antibody to deliver radiation to tumor cells. Dr. Casadevall then
teamed with his colleague Ekaterina Dadachova, Ph.D., an expert
in nuclear medicine and fellow NIAID grantee, to investigate whether
the melanin-binding antibody could be converted into an anti-tumor
drug.

In a study published in October 2004, Dr. Casadevall and Dr. Dadachova,
the study’s lead author, combined the C. neoformans monoclonal
antibodies with radiation to create radiolabeled antibodies. They
then tested these radiolabeled antibodies in mice to determine
their effectiveness in attacking melanoma tumors. Initially, the
mice had melanoma tumors ranging from 0.6 to 1.0 centimeters (cm)
in diameter. After receiving a single dose of the radiolabeled
antibodies, tumor growth was completely inhibited and near total
tumor regression occurred in those animals with smaller tumors
(0.6 to 0.7 cm in diameter). Further, the treated mice showed no
signs of kidney or other organ damage and none died during the
30-day study. Conversely, tumors continued to aggressively grow
in the untreated control group and by day 20, all but one of the
eight untreated mice had died.

In November 2006, Pain Therapeutics, Inc., a San Francisco-based
biopharmaceutical company, licensed the radiolabeled monoclonal
antibody technology from the Albert Einstein College of Medicine.
The company intends to begin testing it as a metastatic melanoma
treatment in small human clinical trials in 2007. According to
the American Cancer Society, melanoma accounts for approximately
five percent of all skin cancers but causes roughly 75 percent
of all skin cancer-related deaths.

Dr. Casadevall credits his promising discovery to luck and a hunch
that paid off. “Scientific breakthroughs often occur completely
through serendipity, and this is just one of those instances,” says
Dr. Casadevall. “We’re still working on cryptococcis and developing
a general strategy for using radiolabeled monoclonal antibodies
to fight infectious diseases.”

His laboratory continues to examine the underlying causes of cryptococcosis,
and in continued collaboration with Dr. Dadachova, is exploring
the use of radiolabeled monoclonal antibodies to treat infectious
diseases.

NIAID is a component of the National Institutes of Health.
NIAID supports basic and applied research to prevent, diagnose
and treat infectious diseases such as HIV/AIDS and other sexually
transmitted infections, influenza, tuberculosis, malaria and
illness from potential agents of bioterrorism. NIAID also supports
research on basic immunology, transplantation and immune-related
disorders, including autoimmune diseases, asthma and allergies.
News releases, fact sheets and other NIAID-related materials
are available on the NIAID Web site at http://www.niaid.nih.gov.

The National Institutes of Health (NIH) — The Nation's
Medical Research Agency — includes 27 Institutes and
Centers and is a component of the U.S. Department of Health and
Human Services. It is the primary federal agency for conducting
and supporting basic, clinical and translational medical research,
and it investigates the causes, treatments, and cures for both
common and rare diseases. For more information about NIH and
its programs, visit www.nih.gov.